Epithelial ovarian carcinoma (EOC) is the most common malignant ovarian tumor, representing 80% of all ovarian malignancies (1). EOCs are thought to originate from either the normal ovarian surface epithelium (OSE) itself or from the crypts and inclusion cysts located in the stroma (1). EOCs are heterogeneous and are designated according to their histological subtype: serous, endometrioid, mucinous, clear cell, Brenner, undifferentiated or mixed (association of two or more sub-types) (2, 3). This cancer is often asymptomatic where over 70% of patients with ovarian cancer are diagnosed at an advanced stage of the disease. While up to 80% of the patients will initially respond to treatment, recurrence is generally observed within variable time intervals. Although 10-15% of the patients achieve and maintain a complete response to therapy, the remaining patients show persistent disease or eventually relapse thus requiring additional treatment. In contrast, borderline or low malignant potential (LMP) tumors, which represent 10-20% of all EOCs, have a more favorable prognosis compared to the invasive form of the disease, where the 5-year survival rate falls below 30% (1, 4).
Currently, there is no reliable method for screening early stage ovarian cancer. The clinically used CA125 serum marker (5) combined with trans-vaginal sonography, 3-dimensional ultrasound or power Doppler have yielded only minimal results (6). The reduced efficacy of CA125 for screening is largely related to its poor specificity. While elevated levels of CA125 are generally associated with the malignant disease, increased serum CA125 levels have also been observed with benign conditions (7), non-neoplastic conditions such as first trimester of pregnancy, menstruation, endometriosis, uterine fibrosis, acute salphingitis, hepatic diseases and inflammation of peritoneum, pericardium or pleura as well as with cancers of other sites. In addition, CA125 levels generally fail to rise in early stage disease, and lower levels are also associated with endometrioid and mucinous ovarian tumors (8). Thus, there is a need to develop reliable screening tools for EOC as these would be extremely valuable for improving cancer detection, clinical management and subsequently impact positively on survival.
Microarray technology is a powerful method for the analysis of cancer-specific gene expression by measuring tumor-specific expression of thousands of genes in hundreds of tumors (9), which can then be associated with specific clinical parameters. Candidate genes for diagnostic markers can further be characterized in combination with a large-scale quantitative polymerase chain reaction (Q-PCR) of RNA and immunohistochemical (IHC) analysis of protein expression using tissue arrays. However, such diagnostic techniques are difficult to implement since they require surgery to obtain the epithelial ovarian samples. Alternatively, if the differentially expressed gene encodes for a secreted protein circulating in peripheral blood, such a protein represents a potential serum based marker. The most common approach for testing such peripheral blood markers is through an enzyme-linked immunosorbent assay (ELISA). Although previous studies have investigated the potential of prostasin, osteopontin, mesothelin and HE4 (10-13) as diagnostic markers of EOC, no single marker has been shown to be sufficiently sensitive nor specific for proper diagnosis of ovarian cancer. Various combinations of different tumor markers have shown a higher specificity in differentiating benign from malignant disease (13, 14). However the efficacy and/or sensitivity of these markers were limited to advanced stage serous subtype tumors.
Therefore, ovarian cancer still remains a major source of morbidity and mortality and there is a clear need for the development of novel diagnosis method having the required sensitivity and specificity for early and reliable detection of ovarian cancer.
The present description refers to a number of documents, the content of which is herein incorporated by reference in their entirety.
Other objects, advantages and features of the present invention will become more apparent upon reading of the following non-restrictive description of specific embodiments thereof, given by way of example only with reference to the accompanying drawings.